tbuckley/cabot-search huggingface dataset:
Abstract 759: Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma
Authors: Shifeng Lian, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng
Journal: Cancer Research (2023)

Abstract Background: Genome-wide cell-free DNA fragmentation profiling was suggested to be useful for early cancer detection. However, it still needed to be evaluated using sample before cancer diagnosis. Methods: A prospective cohort with hepatitis B virus (HBV)-seropositive participants were enrolled in 2012 and followed-up biannually with blood sample collections till 31 December 2019. A case-control study with hospital hepatocellular carcinoma (HCC) cases were conducted to identify potential biomarkers for HCC detection (Discovery). We adapted the DELFI method (Cristiano et al, Nature, 2019) and evaluated cfDNA fragmentation profile (AdaptDelfi) for detecting HCC at the Discovery phase and validated AdaptDelfi in an independent prospective population cohort (Validation). Results: Of 18,373 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases. In Discovery, the AdaptDelfi model distinguished HCC cases from controls excellently (AUC [95% confidence interval] = 0.999 [0.997 - 1.0]), while the serum alpha-fetoprotein (AFP) had an AUC of 0.851 (95% CI = 0.796 - 0.906). High AdaptDelfi was associated with advanced tumor stage (P = 0.038). The hazard of death increased in high AdaptDelfi (hazard ratio 2.43, 95% CI = 1.13 - 5.2) after adjustment for tumor stage. In Validation, AdaptDelfi showed slightly increasing performance using pre-HCC samples collected ≥4 years (AUC = 0.530), 3-4 years (0.615), 2-3 years (0.781), 1-2 years (0.711), and 0-1 year (0.770) before diagnosis. These were comparable with the traditional biomarker - AFP that showed corresponding AUCs of 0.521, 0.525, 0.517, 0.575 and 0.727, respectively. Using a fixed cutoff value from Discovery, AdaptDelfi had a specificity of 88.0% and a sensitivity of 32.5% within one year before diagnosis in detecting early HCC, yielding an estimated positive predict value (PPV) of 1.4% (95% CI = 0.8% - 2.4%) among HBV-seropositive male population. Conclusions: The genome-wide cell-free DNA fragmentation is correlated with HCC stage and may be a useful biomarker for diagnosing clinical HCC and predict patient survival. However, the low PPV suggests its utility in HCC screening in high-risk populations so far may be limited. Citation Format: Shifeng Lian, Fang Fang, Zhiwei Liu, Mingfang Ji, Zongli Zheng. Genome-wide cell-free DNA fragmentation in early detection and disease monitoring of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 759.
Abstract 260: Long RNA and DNA sequencing reveals HEK293 diversity between commercial sources
Authors: Laura Blum, Brittany Sexton, Jonathan C. Sanford, Evan Janzen, Luo Sun, Paul A. Koetsier, Keerthana Krishnan, Lynne Apone, Bradley W. Langhorst
Journal: Cancer Research (2023)

Abstract HEK293 cells are used extensively in cancer research, with more than 4800 articles between 2017 and 2022 (PubMed search “cancer[MeSH Major Topic] and hek293”). Studies involving transfection to overexpress, knock down, or modify proteins in these cells are common. While HEK293 cells are relatively easy to grow and maintain, early use of high throughput sequencing Yao-Cheng et. al. identified genomic variability between different sources of cell lines and revealed unexpected details about their developmental lineage (likely adrenal, not kidney)[1]. Genomic or transcriptomic reorganization may complicate interpretation of results from targeted intervention experiments. Here, we evaluate HEK293 cells from various commercial sources using long read sequencing technology. Oxford Nanopore direct cDNA profiling was used to compare isoform usage and examine gene fusions. Long DNA libraries were prepared using a high molecular weight isolation method, sequenced on Oxford Nanopore, and assembled to produce long contiguous fragments. Genome assemblies generated from long read sequencing support the genomic diversity reported by Yao-Cheng et.al, though the specific copy number variants are distinct from those previously reported. Assembled genomes and transcriptomes for these specific lots of HEK293 cells will be available at NCBI. Given the plastic nature of HEK293 cells, we recommend confirmation of genomic and transcriptomic structure of the specific cells in use before and after intervention. [1] Lin, Yao-Cheng, Morgane Boone, Leander Meuris, Irma Lemmens, Nadine Van Roy, Arne Soete, Joke Reumers, et al. “Genome Dynamics of the Human Embryonic Kidney 293 Lineage in Response to Cell Biology Manipulations.” Nature Communications 5, no. 1 (September 3, 2014): 4767. https://doi.org/10.1038/ncomms5767. Citation Format: Laura Blum, Brittany Sexton, Jonathan C. Sanford, Evan Janzen, Luo Sun, Paul A. Koetsier, Keerthana Krishnan, Lynne Apone, Bradley W. Langhorst. Long RNA and DNA sequencing reveals HEK293 diversity between commercial sources [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 260.
Abstract 2831: Enhanced efficacy of HDAC inhibitor panobinostat and ONC206 combined with radiation therapy against human glioblastoma cell lines without H3K27M mutation
Authors: Vida Tajiknia, Wafik El Deiry, Lanlan Zhou
Journal: Cancer Research (2023)

Abstract Background: Glioblastoma multiforme (GBM) is the most common form of malignant brain tumor in adults. The prognosis of GBM is still poor despite first-line therapy, and the median overall survival (OS) is 12-15 months, while the 5-year survival does not exceed 5%. Despite aggressive initial treatment, most patients develop recurrent diseases. Novel drug combinations for malignant CNS tumors are under investigation. Panobinostat is a histone deacetylase inhibitor (HDACi) with antineoplastic and antiangiogenic effects in glioma, and we previously noted synergy with combination of panobinostat and imipridone ONC206. ONC206 is under clinical investigation for treating adult and pediatric brain tumor patients. We decided to investigate the triple combination of ONC206, Panobinostat and radiation against glioma cells. Materials &amp; Methods: We investigated cell viability and drug synergies of ONC206 plus Panobinostat with or without radiation in 4 human GBM cell lines at 72 hours. Results: We identified synergy between impridone ONC206 and Panobinostat which improved with radiation therapy IC50 values of panobinostat and ONC206 against cell lines U138, U87, T98G &amp; U251MG ranges from 29-85 nM &amp; 0.8-1.2 μM, respectively. Synergies between ONC206 and Panobinostat were observed across cell lines with combination indices of &amp;lt;0.5 indicating strong synergy. When treating with 4GY radiation after 48 h, combination index improved. documenting enhanced tumor cell killing of human glioma cells. Conclusion: Our ongoing studies reveal synergy between ONC206, Panobinostat and radiation against GBM cell lines. The enhanced synergy with radiation provides an opportunity to develop a novel treatment combination for high grade glioma with a focus on recurrent GBM. Citation Format: Vida Tajiknia, Wafik El Deiry, Lanlan Zhou. Enhanced efficacy of HDAC inhibitor panobinostat and ONC206 combined with radiation therapy against human glioblastoma cell lines without H3K27M mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2831.
Abstract 5494: Preclinical combination of ONC201 with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival
Authors: Lanlan Zhou, Laura Jinxuan Wu, Jun Zhang, Andrew George, Marina Hahn, Leiqing Zhang, Attila A. Seyhan, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is the most common and lethal primary malignancy of the central nervous system. It is estimated that more than 13,000 new cases of GBM will be diagnosed this year in the United States. Despite multidisciplinary treatments such as surgery, chemotherapy, and radiotherapy, the five-year survival rate for GBM patients is only 6.8 percent and has shown no notable improvement in the last three decades. There have only been five drugs and one device ever approved by the FDA for the treatment of GBM since it was first identified in the scientific literature in the 1920’s. Our in vitro studies suggested that first-in-class small-molecule imipridone TIC10/ONC201 can inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce mitochondrial dysfunction, growth arrest or cell death in GBM cells. Knockdown of ClpP protects GBM cells from ONC201 but not TMZ. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant diffuse midline glioma patients. We hypothesized that ONC201 may synergize with radiotherapy and temozolomide in GBM. GBM mouse orthotopic models were established through intracranial injection of luciferase expressing U251 GBM cells with a KOPF model 940 small animal stereotaxic frame and a Stoelting Quintessential Stereotaxic Injector. Tumor formation and growth was confirmed with bioluminescence imaging. Randomized treatment group mice received weekly treatment of ONC201 (100 mg/kg p.o.) and/or radiotherapy (2 Gy local irradiation) and/or TMZ (20 mg/kg i.p.) for four weeks for long term survival and tumor monitoring or one week for short term biomarker studies. We observed that the triple combination of ONC201, radiotherapy and TMZ significantly prolongs survival and reduces tumor burden compared to single treatment and dual combinations. Short term biomarker studies demonstrated that triple combination treatment decreases tumor cell proliferation, induces more apoptosis and inhibits ClpX to unleash mitochondrial ClpP. Our data support further development of the triple combination regimen of ONC201, TMZ and radiation therapy for GBM first-line treatment. Citation Format: Lanlan Zhou, Laura Jinxuan Wu, Jun Zhang, Andrew George, Marina Hahn, Leiqing Zhang, Attila A. Seyhan, Wafik S. El-Deiry. Preclinical combination of ONC201 with radiotherapy and Temozolomide in a GBM mouse orthotopic model results in reduced tumor burden and prolonged survival. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5494.
Abstract 2633: Zanidatamab zovodotin (ZW49) induces hallmarks of immunogenic cell death and is active in patient-derived xenograft models of gastric cancer
Authors: Stuart D. Barnscher, Andrea Hernández Rojas, Kevin J. Hamblett, Nichole Escalante
Journal: Cancer Research (2023)

Abstract Zanidatamab zovodotin (ZW49) is an antibody drug conjugate (ADC) comprised of a bispecific anti-HER2 IgG1 antibody (ZW25, zanidatamab) conjugated to a microtubule inhibitor auristatin payload (ZD02044) via a protease cleavable linker. Clinical studies of ZW49 in HER2-expressing advanced solid tumors are currently underway (NCT03821233). We have previously presented data illustrating the rapid internalization of ZW49 and the anti-tumor activity of ZW49 in multiple patient-derived xenograft models originating from breast carcinomas. Here we present ZW49’s ability to induce in vitro hallmarks of immunogenic cell death (ICD) including increased calreticulin exposure, increased high mobility group box-1 (HMGB1) exposure, and increased extracellular ATP secretion in a HER2 dependent manner. Additionally, we present the results from a study evaluating the anti-tumor activity of ZW49 in a panel of patient-derived xenografts of gastric cancer. HER2-positive SK-BR-3 and HER2-negative MDA-MB-468 tumor cell lines were treated with ZW49 and cell surface calreticulin was assessed by flow cytometry. ZW49 treatment of SKBR-3 cells induced a significantly higher percentage of cells staining positive for cell surface calreticulin compared to untreated cells. In contrast, ZW49 treatment of MDA-MB-468 cells resulted in no significant difference in the percentage of cells staining positive for calreticulin compared to untreated cells. ZW49 treated HER2-positive cancer cell lines SK-BR-3 and SK-OV-3 induced higher levels of extracellular ATP compared to untreated cells. In the HER2-negative cell line MDA-MB-468, treatment with ZW49 did not alter levels of extracellular ATP compared to untreated cells. ZW49 induced higher levels of HMGB1 in the HER2-positive cancer cell lines SKBR3 and N87 compared to untreated cells, whereas in the HER2-negative cell line MDA-MB-468, ZW49 induced similar levels of HMGB1 to untreated cells. Anti-tumor activity was observed in 5/7 (71%) PDX models of gastric cancer after a single i.v. dose of 6 mg/kg, including in models with moderate and weak HER2 expression. The strong anti-tumor activity of ZW-49 in vivo, together with its ability to induce ICD and potential adaptive immune responses, support ZW49 as a promising ADC for the treatment of HER2-expressing cancers warranting further investigation, including potential combination with checkpoint inhibitors. Citation Format: Stuart D. Barnscher, Andrea Hernández Rojas, Kevin J. Hamblett, Nichole Escalante. Zanidatamab zovodotin (ZW49) induces hallmarks of immunogenic cell death and is active in patient-derived xenograft models of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2633.
Abstract 3957: Anticancer effect of novel 1,4-benzodiazepine derivatives through tubulin polymerization inhibition
Authors: Alzbeta Srovnalova, Jiri Rehulka, Sona Gurska, Pavel Polyshchuk, Sergey Bachinsky, Petr Dzubak, Marian Hajduch
Journal: Cancer Research (2023)

Abstract Benzodiazepines are well known as a key scaffold in medicinal chemistry, providing bioactive compounds for a wide variety of biological targets. Among their primary use as anxiolytics and sedatives, the 1,4-benzodiazepine derivatives and their metabolites play a role as antitumor, antithrombotic, antiviral and antimalarial agents. Recent studies revealed the influence of the benzodiazepine derivatives on microtubule assembly or stability with subsequent mitotic failure. These microtubule-targeting effects were evaluated in novel benzodiazepine derivatives. The antiproliferative activities of novel derivatives were tested against a panel of 10 cancer cell lines and 2 non-cancer cell lines. The compounds with IC50&amp;lt;10 µM were further analyzed for the cell cycle. Flow cytometry and fluorescent cell cycle indicator (FUCCI) assays were performed to evaluate the effects of derivatives on the cell cycle phases. The immunofluorescence alpha-tubulin assay and tubulin polymerization assay were accomplished to detect the changes in the mitosis. Implementation of molecular docking revealed the specific binding site of the derivatives. All tested derivatives reveal the G2/M block in the cell cycle and 3 of them were identified as M-phase blockers. The immunofluorescence alpha-tubulin assay detected the disruption of the cellular microtubule network, and the tubulin polymerization assay uncovered the potential of the tested compounds to inhibit tubulin polymerization. Molecular docking confirms that benzodiazepine derivatives fit the colchicine site best and are partially overlaid with the native colchicine binding pose. This suggests that these compounds may adapt to the tubulin binding site in a conformation induced by colchicine The inhibition of tubulin polymerization by novel derivatives is one of their possible mechanisms of action on antiproliferative effect on cancer cell lines. More rigorous studies will be performed further to establish pose stability and explain structure-activity relationships. This work was supported by European Union - Programme EXCELES, ID Project No. LX22NPO5102, the Czech Ministry of Education, Youth and Sports (CZ-OPENSCREEN - LM2018130, EATRIS-CZ - LM2018133), and by the internal grant of Palacky University Olomouc (IGA_LF_2022_033) and European Regional Development Fund - Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868). Citation Format: Alzbeta Srovnalova, Jiri Rehulka, Sona Gurska, Pavel Polyshchuk, Sergey Bachinsky, Petr Dzubak, Marian Hajduch. Anticancer effect of novel 1,4-benzodiazepine derivatives through tubulin polymerization inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3957.
Abstract 1768: Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models
Authors: Thomas J. Gardner, Adam Litterman, Brenal K. Singh, Luisa Silva, Mukund Hari, Stanley Zhou, Colin Tang, Sahil Joshi, John Gagnon, Oliver Takacsi-Nagy, Jason Hall, Hans Pope, James Zhang, Alma Gomez, Jeremy Chen, Suchismita Mohanty, Vince Thomas, Nicholas Quant, Beatriz Millare, Amy-Jo Casbon, Natalie Bezman, Levi Gray-Rupp, Angela C. Boroughs, W. Nicholas Haining
Journal: Cancer Research (2023)

Abstract T cell exhaustion resulting from chronic antigen stimulation and immunosuppression in the tumor microenvironment (TME) limits CAR T efficacy in the solid tumor setting. We have previously shown that engineering therapeutic T cell products using CRISPR-based gene insertion of a dual shRNA cassette targeting Fas and PTPN2 significantly increased antitumor efficacy of Integrated Circuit T cells (ICTs) in ovarian cancer models. We sought to build on this finding to induce additional gene perturbations that improve the efficacy of ICTs. Transforming growth factor (TGF)-b is an immunosuppressive cytokine that potently inhibits T cell responses and is present at high levels in numerous solid tumors, including renal cell carcinoma (RCC). In order to render ICT cells less susceptible to TGF-b-mediated suppression, we developed a quadruple shRNA cassette that simultaneously targets Fas, PTPN2, and TGFBR. Candidate TGFBR-targeting shRNAs were selected for their ability to reduce surface TGFBR receptor expression and impair proximal (pSMAD) or distal (CD103, PD-1) signaling through TGFBR. While single shRNAs against TGFBR did not rescue ICT cell activity in the presence of TGF-b, likely due to partial knockdown of TGFBR signaling, a cassette encoding two shRNAs against TGFBR restored ICT function to similar levels observed in the absence of TGF-b. The quadruple shRNA cassettes targeting Fas/PTPN2/TGFBR significantly enhanced antitumor activity of ICT cells in multiple xenograft tumor models relative to Fas/PTPN2 cassettes. These results demonstrate the utility of multiplexed shRNA strategies to render therapeutic T cells resistant to orthogonal suppressive pathways in solid tumors. Citation Format: Thomas J. Gardner, Adam Litterman, Brenal K. Singh, Luisa Silva, Mukund Hari, Stanley Zhou, Colin Tang, Sahil Joshi, John Gagnon, Oliver Takacsi-Nagy, Jason Hall, Hans Pope, James Zhang, Alma Gomez, Jeremy Chen, Suchismita Mohanty, Vince Thomas, Nicholas Quant, Beatriz Millare, Amy-Jo Casbon, Natalie Bezman, Levi Gray-Rupp, Angela C. Boroughs, W. Nicholas Haining. Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1768.
Abstract 3596: EMG1 is an rRNA-modifying protein that contributes to breast cancer progression
Authors: Amr R. Elhamamsy, Heba A. Alsheikh, Rajeev S. Samant, Lalita A. Shevde
Journal: Cancer Research (2023)

Abstract The ribosome, a multi-subunit RNA-protein complex, is essential for translation in all cells. Variation in ribosome composition and characteristics has been observed between cell types and under different metabolic conditions; this phenomenon is referred to as "ribosome heterogeneity." Ribosome heterogeneity has been linked to carcinogenesis and cancer progression. One of the major layers of ribosome heterogeneity is the diverse rRNA modifications. To study the impact of rRNA modifications on cancer, we performed a systematic literature search and identified 22 rRNA modifying proteins (RRMPs) that are involved in mediating different modifications of rRNA. We next examined the RRMPs' expression levels and frequency of mutation in different cancer types, with a focus on breast cancer. We see that most malignancies show alterations in RRMPs' expression levels and frequent mutations. Our analysis of gene expression patterns and clinical outcomes in breast cancer has shown that several RRPMs are strongly linked to an aggressive phenotype and a poor prognosis. Our analysis also revealed that EMG1, a N1-specific psuedouridine methyltransferase, is a RRMP with potential roles in cancer progression and metastasis. Our findings pave the way for further research into the role of RRMPs in different cancers as well as the development of therapies that specifically target RRMPs involved in cancer progression. Citation Format: Amr R. Elhamamsy, Heba A. Alsheikh, Rajeev S. Samant, Lalita A. Shevde. EMG1 is an rRNA-modifying protein that contributes to breast cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3596.